OP179 Quantitative Evidence Synthesis Methods For Assessing The Effectiveness Of Treatment Sequences For Clinical And Economic Decision-Making: Methodology Review

IntroductionThe sequential use of alternative treatments for chronic conditions represents a complex, dynamic intervention pathway; previous treatment and patient characteristics affect both choice and effectiveness of subsequent treatments. Evidence synthesis methods that produce the least biased estimates of treatment-sequencing effects are required to inform reliable clinical and policy decision-making. A comprehensive review was conducted to establish what existing methods are available, outline the assumptions they make, and identify their shortcomings.MethodsThe review encompassed both meta-analytic techniques and decision-analytic modelling, any disease condition, and any type of treatment sequence, but not diagnostic tests, screening, or treatment monitoring. It focused on the estimation of clinical effectiveness and did not consider the impact of treatment sequencing on the estimation of costs or utility values.ResultsThe review included ninety-one studies. Treatment-sequencing is usually dealt with at the decision-modelling stage and is rarely addressed using evidence synthesis methodology for clinical effectiveness. Most meta-analyses are of discrete treatments, sometimes stratified by line of therapy. Prospective sequencing trials are scarce. In their absence, there is no single best way to evaluate treatment sequences, rather there is a range of approaches, each of which has advantages and disadvantages and is influenced by the evidence available and the decision problem. Due to the scarcity of data on sequential treatments, modelling studies generally apply simplifying assumptions to data on discrete treatments. A taxonomy for all possible assumptions was developed, providing a unique resource to aid the critique of decision-analytic models.ConclusionsThe evolution of network meta-analysis in HTA demonstrates that clinical and policy decision-making should account for the multiple treatments available for many chronic conditions. However, treatment-sequencing has yet to be accounted for within clinical evaluations. Economic modelling is often based on the simplifying assumption of treatment independence. This can lead to misrepresentation of the true level of uncertainty, potential bias in estimating the effectiveness and cost effectiveness of treatments and, eventually, the wrong decision.

Association between insomnia patients’ pre-treatment characteristics and their responses to distinctive treatment sequences

Study Objectives It is common to provide insomnia patients a second treatment when the initial treatment fails, but little is known about optimal treatment sequences for different patient types. This study examined whether pre-treatment characteristics/traits predict optimal treatment sequences for insomnia patients. Methods A community sample of 211 adults (132 women; Mage = 45.6 ± 14.9 years) with insomnia were recruited. Patients were first treated with behavioral therapy (BT) or zolpidem (Zol). Non-remitting BT recipients were randomized to a second treatment with either Zol or cognitive therapy; non-remitting Zol recipients underwent BT or Trazodone as a second treatment. Remission rates were assessed at the end of the first and second 6-week treatments. We then compared the remission rates of dichotomous groups formed on the basis of gender, age, pretreatment scores on SF36 and Multidimensional Fatigue Scale, the presence/absence of psychiatric/medical comorbidities or pain disorders, and mean subjective sleep duration and efficiency within and across treatment sequences. Results Lower remission rates were noted for those: with a pain disorder, poor mental health perceptions, high MFI fatigue scores, and lower sleep times and efficiencies. Patients with a pain disorder responded best to the BT-to-Zol sequence, whereas patients with more mental impairment, severe fatigue, short sleep, and low sleep efficiency responded poorly to treatment starting with BT. Conclusions Pain, fatigue, poor mental health status, and subjective sleep duration and efficiency all affect response to different insomnia treatment sequences. Findings may guide clinicians in matching insomnia treatments to their patients. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT01651442, Protocol version 4, April 20, 2011, registered June 26, 2012, https://clinicaltrials.gov/ct2/show/NCT01651442?rslt=With&type=Intr&cond=Insomnia&cntry=US&state=US%3ACO&city=Denver&age=12&draw=2&rank=1.

Improving Outcomes for Patients with Multiple Myeloma through the Optimization of Treatment Sequences

Introduction: Multiple myeloma (MM) is an incurable disease characterized by the proliferation of malignant plasma cells within the bone marrow, causing a wide range of burdensome symptoms. Patients initiating treatment typically receive a combination of drugs across various classes with or without autologous stem cell transplantation (ASCT). However, patients will invariably relapse following initial treatment, and often require many lines of drug treatment over the course of their disease. Real-word data showed that a significant proportion of newly diagnosed MM patients that receive frontline (FL) treatment did not receive subsequent treatment. These high attrition rates suggest that using the best treatment upfront is crucial in delaying disease progression. The CASSIOPEIA (transplant-eligible [TE] setting), MAIA and ALCYONE (transplant-ineligible [TIE] setting) trials demonstrate that the addition of daratumumab (DARA) to standard of care treatments in FL significantly improves patient outcomes. Based on data from these trials, the European marketing authorization for DARA has been extended to the FL setting. To ensure the best possible long-term patient outcomes in clinical practice, the availability of new FL treatment options requires a redefinition of treatment patterns. Thus, we aim to investigate whether the adoption of DARA as a FL, as opposed to later-line, treatment of MM leads to better outcomes and improved clinical practice. Methods: In the absence of real-world sequencing data, we developed a clinical sequencing simulation using individual patient data from the DARA trials and indirect comparative evidence, across all indications in MM. We used progression-free survival curves to simulate health state transition probabilities across four lines of active treatment, to capture the efficacy of treatment sequences in MM. Patients start with initiation of FL treatment, and ASCT eligibility determines the sequences patients receive. Clinical expert opinion was sought to determine 1) the full range of meaningful treatment sequences and 2) which of these are used most in Italian clinical practice. Based on the clinical simulation outcomes, we calculated average time spent in each line of treatment, percentage of patients alive at different timepoints, and the total survival for patients initiating a sequence. This analysis included conservative attrition rates from trial data, 14% for TE (CASSIOPEIA) and 24% for TIE (MAIA/ALCYONE), assumed as similar across regimens in each setting. Results: In the TE setting, the best outcomes were achieved when using the DARA-based regimen (DVTd) as FL treatment, followed by either a LEN-based regimen (KRd) or a BOR-based regimen (PVd), resulting in a total survival of 14.2 and 14.1 years, respectively. In the TIE setting, the best outcomes were achieved when DRd or DVMP were used as FL treatment, followed by either a BOR-based regimen (PVd, for DRd) or a LEN-based regimen (KRd, for DVMP), resulting in a total survival of 11.7 and 10.9 years, respectively. In both the FL and second line (2L) settings, there was a clear survival benefit of using DARA. When comparing the DARA-based sequence with the current FL TE benchmark sequence (DVTd + KRd + Pd + Vd versus VTd + DRd + Kd + Pd), an additional survival of 1.5 years was observed in TE patients. When DARA was added to the current FL TIE benchmark sequence (DRd + PVd + Kd + Vd versus VMP + DRd + Kd + Pd), TIE patients lived on average 2.8 years longer. For TE patients, time spent progression-free ranged from an average of 4.83 to 7.99 years at FL, 1.42 to 5.40 years in 2L, 0.23 to 2.24 years in 3L and 0.17 to 1.53 years on 4L. For TIE patients, the variation was higher, leaving more room for optimization: 1.97 to 7.31 years at FL, 0.68 to 4.76 years in 2L, 0.17 to 3.25 years in 3L and 0.19 to 0.51 years in 4L. Conclusion: To our knowledge, this is the first sequencing simulation to consider optimal patient outcomes across several lines of MM treatment. The results show that the longest time in remission is achieved with the use of DARA-based regimens as FL treatment, significantly improving patient outcomes. Time spent progression free decreases with each subsequent line of treatment and the magnitude of the effect seen in the third and fourth treatment lines is not as significant as that of the effect seen in earlier treatment lines. Therefore, patients should be treated with the most effective treatment upfront. Disclosures Petrucci: Celgene: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Karyopharm: Honoraria, Other: Advisory Board. Mendes: Janssen-Cilag Farmacêutica: Current Employment. Boer: Janssen: Consultancy. Casamassima: Janssen: Current Employment. Willis: Janssen: Consultancy. Wadlund: Janssen: Current Employment. Matthijsse: Janssen: Consultancy. Armeni: Astrazeneca: Consultancy; Boehringer Ingelheim: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; Johnson & Johnson: Consultancy; Amgen: Consultancy; Janssen: Consultancy.

Alemtuzumab in a Large Real-Life Cohort: Interim Baseline Data of the TREAT-MS Study

The non-interventional long-Term study foR obsErvAtion of Treatment with alemtuzumab in active relapsing–remitting MS (TREAT-MS) study collects the so far largest real-life cohort regarding utilization, long-term effectiveness, and safety of alemtuzumab, a humanized monoclonal antibody directed against the cell surface glycoprotein CD52, in adult patients with active relapsing–remitting multiple sclerosis (RRMS). An interim analysis of baseline parameters at inclusion of a non-interventional real-world study about alemtuzumab in Germany including previous multiple sclerosis (MS) medication utilization, MS activity, severity, and duration, as well as comorbidities was performed. Of the 883 patients, 71.6% were women. Mean age was 35.7 ± 9.2 years, time since first MS symptoms (=disease duration) is 8.0 ± 6.8 years, and Expanded Disability Status Scale (EDSS) is 2.7 ± 1.8 points (range, 0.0–7.5 points). The number of relapses in the 12 and 24 months prior to inclusion were 1.6 ± 1.2 and 2.2 ± 1.8, respectively. Of the patients, 14.4% were treatment naive, while for the majority, a wide spectrum of MS disease-modifying treatments (DMTs) and treatment sequences were documented. Overall, interferon beta (IFN-beta) was reported most frequently (52.4%), followed by fingolimod (35.2%), natalizumab (34.9%), and glatiramer acetate (28.9%). Patients with longer disease duration and higher EDSS had a higher number of previous DMTs. Compared to the pivotal phase 2/3 studies, RRMS patients starting alemtuzumab treatment had a longer disease duration in real-world conditions. There was variety of different treatment sequences before the final switch to alemtuzumab. In the future, linking these treatment sequences or other baseline characteristics with effectiveness and safety outcomes might be useful to support treatment decisions. Registered at Paul-Ehrlich-Institut under NIS 281.

A Sequential Multiple Assignment Randomized Trial (SMART) study of medication and CBT sequencing in the treatment of pediatric anxiety disorders

Background Treatment of a child who has an anxiety disorder usually begins with the question of which treatment to start first, medication or psychotherapy. Both have strong empirical support, but few studies have compared their effectiveness head-to-head, and none has investigated what to do if the treatment tried first isn’t working well—whether to optimize the treatment already begun or to add the other treatment. Methods This is a single-blind Sequential Multiple Assignment Randomized Trial (SMART) of 24 weeks duration with two levels of randomization, one in each of two 12-week stages. In Stage 1, children will be randomized to fluoxetine or Coping Cat Cognitive Behavioral Therapy (CBT). In Stage 2, remitters will continue maintenance-level therapy with the single-modality treatment received in Stage 1. Non-remitters during the first 12 weeks of treatment will be randomized to either [1] optimization of their Stage 1 treatment, or [2] optimization of Stage 1 treatment and addition of the other intervention. After the 24-week trial, we will follow participants during open, naturalistic treatment to assess the durability of study treatment effects. Patients, 8–17 years of age who are diagnosed with an anxiety disorder, will be recruited and treated within 9 large clinical sites throughout greater Los Angeles. They will be predominantly underserved, ethnic minorities. The primary outcome measure will be the self-report score on the 41-item youth SCARED (Screen for Child Anxiety Related Disorders). An intent-to-treat analysis will compare youth randomized to fluoxetine first versus those randomized to CBT first (“Main Effect 1”). Then, among Stage 1 non-remitters, we will compare non-remitters randomized to optimization of their Stage 1 monotherapy versus non-remitters randomized to combination treatment (“Main Effect 2”). The interaction of these main effects will assess whether one of the 4 treatment sequences (CBT➔CBT; CBT➔med; med➔med; med➔CBT) in non-remitters is significantly better or worse than predicted from main effects alone. Discussion Findings from this SMART study will identify treatment sequences that optimize outcomes in ethnically diverse pediatric patients from underserved low- and middle-income households who have anxiety disorders. Trial registration This protocol, version 1.0, was registered in ClinicalTrials.gov on February 17, 2021 with Identifier: NCT04760275.

P477 Assessment of treatment sequence and real-world outcomes in patients with Ulcerative Colitis

Background Several therapies are available to manage moderately to severely active ulcerative colitis (UC); however, little is known about the impact of treatment sequence on patient outcomes. Using real-world data, we assessed the outcomes of patients treated with different UC treatment sequences in routine clinical practice in the USA with the aim of determining the optimal position of vedolizumab within the current UC treatment paradigm. Methods This analysis used deidentified claims and clinical data from the Optum Research Database between 2016 and 2019. Patients diagnosed with UC were identified using International Classification of Diseases, Tenth Revision codes, and UC treatments were identified using National Drug Codes. Two scenarios of treatment sequences were analysed: with (S1) or without (S2) the inclusion of immunomodulator (IM) therapy (Table). Patients were matched on baseline age, sex and race using nearest neighbour propensity score matching. Outcomes, including colectomy-related procedure, disease flare defined as a relevant diagnostic/imaging procedure, UC-related hospitalization, UC-related laboratory test abnormality and all-cause death, were described for each of the treatment sequences (Figure 1). Results Of a total of 143 678 patients diagnosed with UC, 3291 were treated with vedolizumab and an IM and/or an anti-tumour necrosis factor (TNF) therapy. Patients who received vedolizumab before an IM and/or anti-TNF therapy (S1a and S2a) had better outcomes than those who received vedolizumab after one or both of these therapies, including a numerically lower rate of UC-related hospitalizations, colectomies, disease flares, UC-related laboratory test abnormalities and all-cause death (Figures 2 and 3). Conclusion Given the increasing number of therapies available for the management of UC, it is important to understand the impact of treatment sequence on outcomes. Clinical trial evidence suggests that patients with UC may experience better outcomes when vedolizumab is used prior to anti-TNF therapy. This observation is consistent with the findings of this analysis of real-world outcomes in patients with UC who received treatments in different sequences. Owing to the nature of the data, the population could not be stratified by disease activity. Future work will aim to further characterize outcomes associated with different treatment sequences in patients with moderately to severely active UC and include newly available therapies.